Substituted and unsubstituted benzooxathiazoles and compounds derived therefrom

ABSTRACT

The invention relates to substituted and unsubstituted 3H-benzo[1,2,3]oxathiazole 2,2-dioxides, 1,3-dihydrobenzo[1,2,5]thiadiazole 2,2-dioxides and 1,3-dihydrobenzo[c]isothiazole 2,2-dioxides, to their preparation and to their use in medicaments.

[0001] This application claims priority to German Patent Application10038709.8-44, filed Aug. 9, 2000, which is hereby incorporated byreference, in its entirety.

BACKGROUND OF THE INVENTION

[0002] 1 Field of the Invention

[0003] The present invention relates to substituted and unsubstituted3H-benzo-[1,2,3]oxathiazole 2,2-dioxides,1,3-dihydrobenzo[1,2,5]thiadiazole 2,2-dioxides and1,3-dihydrobenzo[c]isothiazole 2,2-dioxides, to their preparation and totheir use in medicaments

[0004] 2. Description of the Related Art

[0005] Aminobenzosultam derivatives acting as lipoxygenase inhibitorsare known (WO 92/05164). Also known is the use of correspondingbifunctional derivatives as charge transporters in photoreceptors (JP95/325942). Andersen et al. described the synthesis oftoluenesulfonyl-protected derivatives and studies of reactions of thesederivatives with nucleophiles (K. Andersen et al., J. Phys. Org. Chem.,10, 175-181 (1997); K. Andersen et al., J Org. Chem., 60, 2003-2007(1995)).

SUMMARY OF THE INVENTION

[0006] It was an object of the present invention to provide novelsubstituted and unsubstituted benzooxathiazoles and their preparationand use as pharmaceutically active compounds. In particular, it was anobject to provide novel substituted and unsubstituted benzooxathiazolesfor treating type 1 and type 2 diabetes, insulin resistance andpathological obesity.

[0007] The present invention relates to compounds of the formula I

[0008] in which

[0009] X is CH₂, O, N;

[0010] Y is CH₂, O, N;

[0011] R1, R2, R3 are each independently of one another

[0012] H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;

[0013] COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl,CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0014] O—(C₁-C₆)alkyl;

[0015] (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH,(C₁-C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienylor pyridyl and the aryl moiety may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0016] Phenyl, biphenyl, 1- or 2-naphthyl, 2-,3- or 4-pyridyl, 2- or3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl,pyridyl, furanyl or thienyl rings may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0017] (C₃-C₁₈)cycloalkyl, where in the alkyl radicals one or morehydrogens may be replaced by fluorine or one hydrogen may be replaced byOH, (C₁-C₆)alkyl-phenyl or O—(C₁-C₆)alkyl-phenyl,

[0018] NCO, NSO₃—(C₁-C₁₀)alkyl; or in each case two of the radicals R1and R2 or R2 and R3 or R1 and R3 together form a fused aryl radical,where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and thearyl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH,COO(C₁-C₆)alkyl, CONH₂;

[0019] or its physiologically acceptable salts or prodrugs.

[0020] The invention preferably relates to compounds of the formula Iwherein

[0021] X is O, N;

[0022] Y is O, N;

[0023] R1 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;

[0024] COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl,CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0025] O—(C₁-C₆)alkyl;

[0026] (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH,(C₁-C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienylor pyridyl and the aryl moiety may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0027] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl,pyridyl, furanyl or thienyl rings may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0028] (C₃-C₁₈)cycloalkyl, where in the alkyl radicals one or morehydrogens may be replaced by fluorine or one hydrogen may be replaced byOH, (C₁-C₆)alkyl-phenyl or O—(C₁-C₆)alkyl-phenyl,

[0029] NCO, NSO₃—(C₁-C₁₀)alkyl;

[0030] R2 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;

[0031] COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl,CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO-(C₁-C₁₀)alkyl or O—(C₁-CO₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-CO₆)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0032] O—(C₁-C₆)alkyl;

[0033] (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH,(C₁-C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienylor pyridyl and the aryl moiety may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0034] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl,pyridyl, furanyl or thienyl rings may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0035] (C₃-C₁₈)cycloalkyl, where in the alkyl radicals one or morehydrogens may be replaced by fluorine or one hydrogen may be replaced byOH, (C₁-C₆)alkyl-phenyl or O—(C₁-C₆)alkyl-phenyl,

[0036] NCO, NSO₃—(C₁-C₁₀)alkyl;

[0037] R3 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;

[0038] COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl,CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0039] O—(C₁-C₆)alkyl;

[0040] (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH,(C₁-C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienylor pyridyl and the aryl moiety may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0041] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl,pyridyl, furanyl or thienyl rings may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0042] (C₃-C₁₈)cycloalkyl, where in the alkyl radicals one or morehydrogens may be replaced by fluorine or one hydrogen may be replaced byOH, (C₁-C₆)alkyl-phenyl or O—(C₁-C₆)alkyl-phenyl, NCO,NSO₃—(C₁-C₁₀)alkyl;

[0043] or its physiologically acceptable salts or prodrugs.

[0044] The invention furthermore preferably relates to compounds of theformula I wherein

[0045] X is O, N;

[0046] Y is N;

[0047] R1 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;

[0048] COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl,CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0049] O—(C₁-C₆)alkyl;

[0050] (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH,(C₁-C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienylor pyridyl and the aryl moiety may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0051] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl,pyridyl, furanyl or thienyl rings may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0052] (C₃-C₁₈)cycloalkyl, where in the alkyl radicals one or morehydrogens may be replaced by fluorine or one hydrogen may be replaced byOH, (C₁-C₆)alkyl-phenyl or O—(C₁-C₆)alkyl-phenyl,

[0053] NCO, NSO₃—(C₁-C₁₀)alkyl;

[0054] R2 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;

[0055] COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl,CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0056] O—(C₁-C₆)alkyl;

[0057] (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH,(C₁-C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienylor pyridyl and the aryl moiety may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(CG-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0058] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl,pyridyl, furanyl or thienyl rings may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0059] (C₃-C₁₈)cycloalkyl, where in the alkyl radicals one or morehydrogens may be replaced by fluorine or one hydrogen may be replaced byOH, (C₁-C₆)alkyl-phenyl or O—(C₁-C₆)alkyl-phenyl,

[0060] NCO, NSO₃—(C₁-C₁₀)alkyl;

[0061] R3 is COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl,CONH(C₁-C₁₆)alkenyl, CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono-to trisubstituted by O-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0062] O—(C₁-C₆)alkyl;

[0063] (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH,(C₁-C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienylor pyridyl and the aryl moiety may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂—;

[0064] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl,pyridyl, furanyl or thienyl rings may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0065] (C₃-C₁₈)cycloalkyl, where in the alkyl radicals one or morehydrogens may be replaced by fluorine or one hydrogen may be replaced byOH, (C₁-C₆)alkyl-phenyl or O—(C₁-C₆)alkyl-phenyl, NCO,NSO₃—(C₁-C₁₀)alkyl;

[0066] or its physiologically acceptable salts or prodrugs.

[0067] The invention furthermore preferably relates to compounds of theformula I wherein

[0068] X is O;

[0069] Y is N;

[0070] R1 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;

[0071] COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl,CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0072] O—(C₁-C₆)alkyl;

[0073] (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH,(C₁-C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienylor pyridyl and the aryl moiety may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0074] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl,pyridyl, furanyl or thienyl rings may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0075] (C₃-C₁₈)cycloalkyl, where in the alkyl radicals one or morehydrogens may be replaced by fluorine or one hydrogen may be replaced byOH, (C₁-C₆)alkyl-phenyl or O—(C₁-C₆)alkyl-phenyl,

[0076] NCO, NSO₃—(C₁-C₁₀)alkyl;

[0077] R2 is F, Cl, Br, I, NH₂, OH, NO₂, COOH;

[0078] COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl,CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0079] O—(C₁-C₆)alkyl;

[0080] (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH,(C₁-C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienylor pyridyl and the aryl moiety may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; Phenyl, biphenyl, 1-or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl,where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl ringsmay in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH,COO(C₁-C₆)alkyl, CONH₂;

[0081] (C₃-C₁₈)cycloalkyl, where in the alkyl radicals one or morehydrogens may be replaced by fluorine or one hydrogen may be replaced byOH, (C₁-C₆)alkyl-phenyl or O—(C₁-C₆)alkyl-phenyl,

[0082] NCO, NSO₃—(C₁-C₁₀)alkyl;

[0083] R3 is COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl,CONH(C₁-C₁₆)alkenyl, CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono-to trisubstituted by O-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0084] O—(C₁-C₆)alkyl;

[0085] (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH,(C₁-C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienylor pyridyl and the aryl moiety may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0086] Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl,pyridyl, furanyl or thienyl rings may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;

[0087] (C₃-C₁₈)cycloalkyl, where in the alkyl radicals one or morehydrogens may be replaced by fluorine or one hydrogen may be replaced byOH, (C₁-C₆)alkyl-phenyl or O—(C₁-C₆)alkyl-phenyl,

[0088] NCO, NSO₃—(C₁-C₁₀)alkyl;

[0089] or its physiologically acceptable salts or prodrugs.

[0090] The invention further relates to a method of inhibiting a PTPase,preferentially PTP1B, CD45, LAR, SHP-1, SHP-2, PTPa or HePTP, comprisingadministering to a subject in need thereof an effective amount of one ormore compounds of formula 1 as described above.

[0091] The invention further relates to a method of treating type 1diabetes, type 2 diabetes, insuling resistance, or pathological obesitycomprising administering to a subject in need thereof an effectiveamount of one or more compounds of formula 1 as described above.

[0092] The invention still further relates to a method of preparing apharmaceutical composition comprising the steps of mixing one or morecompounds of formula 1 with one or more pharmaceutically acceptableexcipients and bringing this mixture into a form suitable foradministration.

[0093] Other compounds, features and advantages of the present inventionwill become apparent from the following detailed description. It shouldbe understood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

[0094] In a compound of the formula I, X and Y in preferred embodimentsmay in each case independently of one another be CH₂, O or N.

[0095] The invention relates to compounds of the formula I, in the formof their racemates, racemic mixtures and pure enantiomers, and to theirdiastereomers and mixtures thereof.

[0096] The alkyl, alkenyl and alkynyl radicals in the substituents R1,R2 and R3 can be either straight-chain or branched.

[0097] On account of their higher water solubility, pharmaceuticallyacceptable salts are particularly suitable for medicinal applicationscompared with the starting materials or base compounds. These salts musthave a pharmaceutically acceptable anion or cation. Suitablepharmaceutically acceptable acid addition salts of the compoundsaccording to the invention are salts of inorganic acids, such ashydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoricacid, nitric acid, sulfonic acid and sulfuric acid, and of organicacids, such as, for example, acetic acid, benzenesulfonic acid, benzoicacid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid,glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleicacid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonicacid, tartaric acid and trifluoroacetic acid. For medicinal purposes,the chlorine salt is particularly preferred. Suitable pharmaceuticallyacceptable basic salts are ammonium salts, alkali metal salts (such assodium salts and potassium salts) and alkaline earth metal salts (suchas magnesium salts and calcium salts).

[0098] Salts having a pharmaceutically acceptable anion are likewiseincluded in the scope of the invention as useful intermediates for theproduction or purification of pharmaceutically acceptable salts and/orfor use in nontherapeutic, for example in-vitro, applications.

[0099] Salts of chemical compounds of the formula I can be preparedusing customary methods familiar to the person skilled in the art. Asalt can be prepared, for example, by combining a chemical compound ofthe formula I with an inorganic or organic acid or base in a solvent ordiluent.

[0100] The term “physiologically functional derivative” used hererelates to any physiologically acceptable derivative of a compound ofthe formula I according to the invention, for example an ester, which onadministration to a mammal, such as, for example, man, is able (directlyor indirectly) to form a compound of the formula I or an activemetabolite thereof.

[0101] The physiologically functional derivatives also include prodrugsof the compounds according to the invention. Such prodrugs can bemetabolized in vivo to a compound according to the invention. Theseprodrugs can themselves be active or inactive.

[0102] The compounds according to the invention can also be present invarious polymorphic forms, for example as amorphous and crystallinepolymorphic forms. All polymorphic forms of the compounds according tothe invention are included in the scope of the invention and are afurther aspect of the invention.

[0103] Hereinbelow, all references to “compound(s) according to formula(I)” refer to a compound/compounds of the formula (I) as describedabove, and to their salts, solvates and physiologically functionalderivatives as described herein.

[0104] The amount of a compound according to formula (I) which isnecessary in order to achieve the desired biological effect is dependenton a number of factors, for example the specific compound selected, theintended use, the manner of administration and the clinical condition ofthe patient. In general, the daily dose is in the range from 0.3 mg to100 mg (typically from 3 mg to 50 mg) per day per kilogram ofbodyweight, for example 3-10 mg/kg/day. An intravenous dose can be, forexample, in the range from 0.3 mg to 1.0 mg/kg, which can be suitablyadministered as an infusion of 10 ng to 100 ng per kilogram per minute.Suitable infusion solutions for these purposes can contain, for example,from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter.Individual doses can contain, for example, from 1 mg to 10 g of theactive compound. Thus, ampoules for injections can contain, for example,from 1 mg to 100 mg, and orally administrable individual doseformulations, such as, for example, tablets or capsules, can contain,for example, from 1.0 to 1 000 mg, typically from 10 to 600 mg. In thecase of pharmaceutically acceptable salts, the abovementioned weightdetails relate to the weight of the dihydrothiazolium ion derived fromthe salt. For the prophylaxis or therapy of the abovementionedconditions, the compounds according to formula (I) can be usedthemselves as the compound, but they are preferably present in the formof a pharmaceutical composition with a tolerable excipient. Theexcipient must of course be tolerable, in the sense that it iscompatible with the other constituents of the composition and is notharmful to the patient's health. The excipient can be a solid or aliquid or both and is preferably formulated with the compound as anindividual dose, for example as a tablet which can contain from 0.05% to95% by weight of the active compound. Further pharmaceutically activesubstances can also be present, including further compounds according toformula (I). The pharmaceutical compositions according to the inventioncan be prepared by one of the known pharmaceutical methods, whichessentially consist in mixing the constituents with pharmacologicallyacceptable excipients and/or auxiliaries.

[0105] Pharmaceutical compositions according to the invention are thosewhich are suitable for oral, rectal, topical, peroral (e.g. sublingual)and parenteral (e.g. subcutaneous, intramuscular, intradermal orintravenous) administration, although the most suitable manner ofadministration in each individual case is dependent on the nature andseverity of the condition to be treated and on the nature of thecompound according to formula (I) used in each case. Sugar-coatedformulations and sugar-coated delayed release formulations are alsoincluded in the scope of the invention. Acid-resistant and entericformulations are preferred. Suitable enteric coatings include celluloseacetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

[0106] Suitable pharmaceutical compounds for oral administration can bepresent in separate units, such as, for example, capsules, cachets,lozenges or tablets which in each case contain a certain amount of thecompound according to formula (I); as powders or granules; as solutionor suspension in an aqueous or nonaqueous liquid; or as an oil-in-wateror water-in-oil emulsion. As already mentioned, these compositions canbe prepared by any suitable pharmaceutical method which includes a stepin which the active compound and the excipient (which can consist of oneor more additional constituents) are brought into contact. In general,the compositions are prepared by uniform and homogeneous mixing of theactive compound with a liquid and/or finely divided solid excipient,after which the product is shaped, if necessary. Thus a tablet, forexample, can be prepared by pressing or shaping a powder or granules ofthe compound, if appropriate with one or more additional constituents.Pressed tablets can be prepared by tableting the compound infree-flowing form, such as, for example, in a powder or granules, ifappropriate mixed with a binder, lubricant, inert diluent and/or one (anumber of) surface-active/dispersing agent(s) in a suitable machine.Shaped tablets can be prepared by shaping the pulverulent compound,moistened with an inert liquid diluent, in a suitable machine.

[0107] Pharmaceutical compositions which are suitable for peroral(sublingual) administration include lozenges which contain a compoundaccording to formula (I) with a flavoring, customarily sucrose and gumarabic or tragacanth, and pastilles which include the compound in aninert base such as gelatin and glycerol or sucrose and gum arabic.

[0108] Suitable pharmaceutical compositions for parenteraladministration preferably include sterile aqueous preparations of acompound according to formula (I), which are preferably isotonic withthe blood of the intended recipient. These preparations are preferablyadministered intravenously, although the administration can also takeplace subcutaneously, intramuscularly or intradermally as an injection.These preparations can preferably be prepared by mixing the compoundwith water and rendering the obtained solution sterile and isotonic withthe blood. Injectable compositions according to the invention in generalcontain from 0.1 to 5% by weight of the active compound.

[0109] Suitable pharmaceutical compositions for rectal administrationare preferably present as individual dose suppositories. These can beprepared by mixing a compound according to formula (I) with one or moreconventional solid excipients, for example cocoa butter, and shaping theresulting mixture.

[0110] Suitable pharmaceutical compositions for topical application tothe skin are preferably present as ointment, cream, lotion, paste,spray, aerosol or oil. Excipients which can be used are petroleum jelly,lanolin, polyethylene glycols, alcohols and combinations of two or moreof these substances. The active compound is in general present in aconcentration of from 0.1 to 15%, for example of from 0.5 to 2%, byweight of the composition.

[0111] Transdermal administration is also possible. Suitablepharmaceutical compositions for transdermal administration can bepresent as individual patches which are suitable for long-term closecontact with the epidermis of the patient. Such patches suitably containthe active compound in an optionally buffered aqueous solution,dissolved and/or dispersed in an adhesive or dispersed in a polymer. Asuitable active compound concentration is from about 1% to 35%,preferably from about 3% to 15%. As a particular possibility, the activecompound can be released by electrotransport or iontophoresis, asdescribed, for example, in Pharmaceutical Research, 2(6): 318 (1986).

[0112] The invention furthermore relates to a process for preparing thecompounds of the formula I, which comprises obtaining the compounds ofthe formula I in such a way that the procedure is according to thefollowing reaction scheme:

[0113] A benzylidenediamine of the formula II in which R1, R2 and R3 areas defined in the sections above is reacted with sulfonediamine. Inparticular, it is possible to prepare a chemical compound of the formulaI in which X is N and Y is N in this manner.

[0114] It is also possible to prepare a compound of the presentinvention by reacting a 2-aminophenol of the formula III whose N groupis protected and whose substituents R1, R2 and R3 are as defined underformula I with sulfuryl chloride, followed by removal of the protectivegroup. The N group of the 2-aminophenol of the formula III is preferablyprotected by p-toluenesulfonyl.

[0115] Alternatively, a 2-aminophenol of the formula III in which the2-aminophenol is present without protective group is used as startingmaterial. This 2-aminophenol of the formula III whose N group is notprotected and whose substituents R1, R2 and R3 are each defined as inclaim 1 is treated with sulfonyidiimidazole under basic conditions. Thebase used can, for example, be triethylamine, a Hunig base or DBU(1,5-diazabicyclo[4.3.0]non-5-ene).

[0116] It is also possible to prepare a compound of the presentinvention by a process in which initially a 1-bromomethyl-2-nitrobenzeneof the formula IV

[0117] whose substituents R1, R2 and R3 are as defined under formula Iwith Na₂SO₃ (sodium sulfite) to give a compound of the formula V whichis then converted by reduction of the nitro group into the correspondinganiline. A compound of the formula I is finally obtained by heating thisaniline of the compound of the formula V.

[0118] The invention also relates to a pharmaceutical composition ormedicament which comprises at least one of the compounds of the formulaI and/or its physiologically acceptable salts and/or their prodrugs and,if appropriate, additional excipients.

[0119] The compounds of the formula I, and/or their physiologicallyacceptable salts and/or their prodrugs can be used for preparingmedicaments.

[0120] Such medicaments are suitable, in particular, for treating type 1and 2 diabetes, insulin resistance and pathological obesity. Inaddition, they are also suitable for treating elevated blood lipidlevels, hypertension, atherosclerosis, immune system dysfunctions,autoimmune diseases, allergic diseases such as asthma, osteoporosis,disturbed proliferation, such as cancer and psoriasis, diseases wherethe production of growth factors, hormones or cytokines which effect therelease of growth hormones is reduced or increased, infectious diseasesor disorders of the nervous system, such as Alzheimer's disease andschizophrenia.

[0121] The compounds of the formula I, and/or their physiologicallyacceptable salts and/or their prodrugs can furthermore be used forpreparing a medicament which inhibits a PTPase. Suitable PTPases are, inparticular, PTP1B, CD45, LAR, SHP-1, SHP-2, PTPa or HePTP.

[0122] Finally, compounds of the formula I and/or their physiologicallyacceptable salts and/or their prodrugs can be used for preparing amedicament for the treatment of diseases, in particular, type 1 and 2diabetes, insulin resistance, pathological obesity, elevated blood lipidlevels, hypertension, atherosclerosis, immune system dysfunctions,autoimmune diseases, allergic diseases such as asthma, osteoporosis,disturbed proliferation, such as cancer and psoriasis, diseases wherethe production of growth factors, hormones or cytokines which effect therelease of growth hormones is reduced or increased, disorders of thenervous system such as Alzheimer's disease and schizophrenia andinfectious diseases.

[0123] The invention relates to the preparation of a medicamentcomprising at least one compound of this invention, which comprisesmixing the active compound with a pharmaceutically acceptable excipient,and bringing this mixture into a form suitable for administration.

[0124] List of abbreviations: aa amino acids DBU1,5-diazabicyclo(4.3.0)non-5-ene DMSO dimethyl sulfoxide DITdithiotreitol EDTA ethylenediaminetetraacetic acid EtOAc ethyl EGTAethylenebis(oxyethylenenitrilo)tetraacetic acid h hour HPLC highpressure liquid chromatography MeOH methanol MOI multiplicity ofinfection MS mass spectroscopy NMR nuclear magnetic resonance PAGEpolyacrylamide gel electrophoresis RP reversed phase RT room temperatureSDS sodium dodecylsulfate TFA trifluoroacetic acid

[0125] The present invention, thus generally described, will beunderstood more readily by reference to the examples listed below, whichserve to illustrate the present invention without limiting it.

EXAMPLES

[0126]

TABLE 1 Compound R1 R2 R3 X Y 1 7-H 6-H 5-H N N 2 7-H 6-H 5-CH₃ N O 37-H 6-H 5-H O N 4 In positions 4 and 5, in each case two O N radicals R1and R2 or R2 and R3 or R1 and R3 together form a fused benzene radical;the respective remaining radical located in position 7 or 6 is H 5 7-H6-NO₂ 5-H O N 6 7-H 6-NH₂ 5-H O N 7 7-H 6-H 5-COO(CH₃) O N 8 7-H 6-H5-COOH O N 9 7-H 6-H 5-CON O N (CH₂—CH₂— phenyl-3,4-O- CH₂-phenyl) 107-H 6-H 5-CON O N (CH₂-phenyl-4- O—(CH₂)₇—CH₃) 11 7-H 6-H 5-CON O N((CH₂)₁₅—CH₃) 12 7-H 6-H 5-COO(CH₃) N O 13 7-H 6-H 5-COOH N O 14 7-H 6-H5-CON N O (CH₂—CH₂— phenyl-3,4-O- CH₂-phenyl) 15 7-H 6-H 5-CON N O (CH₂-benzimidazolyl -2,5-S-phenyl)

[0127] Inhibitors of phosphatases are described, inter alia, inWO97/3974 (cinnamic acid derivatives as inhibitors of PTP) which ishereby incorporated herein by reference. Unspecific phosphataseinhibition by vanadium oxo complexes and other vanadium complexesresults in improved insulin resistance.

[0128] Enzymatic test systems for detecting phosphatase inhibition

[0129] In an in vitro assay, the compounds of the formula I were testedfor their phosphatase-inhibiting action. Enzyme preparation and assaywere carried out as follows.

[0130] Obtaining the Enzyme Preparation:

[0131] A) Cell Culture:

[0132] Sf9 cells (=Spodoptera frugiperda cell type; obtainable fromInvitrogen) are cultivated in spinner flasks at 28° C. in Grace'ssupplemented medium (Gibco-BRL) with 10% heat-inactivated fetal calfserum (Gibco-BRL) according to the protocol of Summers and Smith (AManual for Methods for Baculovirus Vectors and Insect Culture Procedures[Bulletin No. 15555]. Texas A & M University, Texas AgriculturalExperiment Station, College Station, TX, 1987). Construction ofrecombinant Baculovirus transfer vectors: cDNA encoding the regulatoryand catalytic domains of human PTP1 B, but without the carboxy-terminalhydrophobic region (corresponding to 1-299 aa) was obtained viapolymerase chain reaction using primers with added donation sites andsuitable cDNA matrices (obtainable, for example, from Invitrogen) andthen cloned in Baculovirus expression vectors (Amersham PharmaciaBiotech.). The recombinant Baculoviruses were prepared using theBac-to-Bac Baculovirus expression system (obtainable from Gibco-BRL).The gene was cloned into the pFASTBAC donor plasmid (obtainable fromLife Technologies). The resulting plasmid was transformed into competentDH10BAC Escherichia coli cells (obtainable from Life Technologies).Following transposition and antibiotic selection, the recombinantplasmid DNA of selected E. coli colonies was isolated and then used forthe transfection of Sf9 insect cells. The virus particle in thesupernatant medium was amplified three times, up to a viral stock volumeof 500 ml.

[0133] B) Production of Recombinant Protein:

[0134] Baculovirus infection of a 500 ml spinner culture of Sf9 cellswas carried out essentially as described by Summers and Smith (seeabove). At a density of 1-3×10⁶ cells/ml, Sf9 cells were pelleted bycentrifugation at 300 g for 5 min, the supernatant was removed and thecells were resuspended at a density of 1×10⁷ cell/ml in a suitablerecombinant viral stock (MOI 10). The culture was shaken carefully atroom temperature for 1.5 h and fresh medium was then added to a celldensity of 1×10⁶ cells/ml. The cells were then cultivated in suspensionat 28° C. for suitable periods following postinfection.

[0135] C) Cellular Fractionation and Total Cell Extracts of Infected Sf9Cells:

[0136] Following postinfection, aliquots were subjected to an analysisof protein expression by SDS-PAGE and Western blot analysis. Cellularfractionation was carried out as described (Cromlish, W. and Kennedy, B.Biochem. Pharmacol. 52: 1777-1785, 1996). Total cell extracts wereobtained of 1 ml aliquots of the infected Sf9 cells after certainintervals postinfection. The pelleted cells (300×g, 5 min) were washedonce in phosphate-buffered saline (4° C.), resuspended in 50 μl of waterand broken up by repeated freezing/thawing. Protein concentrations weredetermined using the Bradford method, with bovine serum albumin asstandard.

[0137] Assay:

[0138] A) Dephosphorylation of a Phosphopeptide:

[0139] This assay is based on the release of phosphate from a consensussubstrate peptide which is detected in the nanomolar concentration rangeby the Malachite Green/ammonium molybdate method (Lanzetta, P. A.,Alvarez, L. J., Reinach, P. S., Candia, O. A. Anal Biochem. 100: 95-97,1979) adapted for the microtiter plate format. Thedodecatrisphosphopeptide, TRDIYETDYYRK (Biotrend, Cologne) correspondsto the amino acids 1142-1153 of the catalytic domain of the insulinreceptor and is (auto)phosphorylated on the tyrosine residues 1146,1150, and 1151. The recombinant hPTP1B was diluted with assay buffer (40mM Tris/HCl, pH 7.4, 1 mM EDTA, 20 mM DTT), corresponding to an activityof 1000-1500 nmol/m in/mg of protein, and then preincubated (a 20 μlportion, 15 min, 30° C.) in the absence or presence of the testsubstance (5 μl) in the desired concentration (final concentration DMSO2% max.) in a total volume of 90 μl (assay buffer). To initiate thedephosphorylation reaction, the peptide substrate (10 μl, pre-warmed to30° C.) was added to the preincubated enzyme preparation with or withouttest substance (final concentration 02-200 μM), and the incubation wascontinued for 1 h. The reaction was terminated by addition of 100 μl ofMalachite Green hydrochloride (0.45%, 3 parts), ammonium molybdatetetrahydrate (4.2% in 4 N HCl, 1 part) and 0.5% of Tween 20 as stopsolution. Following 30 min of incubation at 22° C. for colordevelopment, the absorption at 650 nm was determined using a microtiterplate reader (Molecular Devices). Samples and blank values weredetermined in three replications. The PTP1B activity was calculated asnanomoles of released phosphate per min and mg of protein usingpotassium phosphate as standard. The inhibition of recombinant hPTP1B bytest substances was calculated as a percentage of the phosphatasecontrol. The IC₅₀ values show significant correlation with afour-parameter nonlinear logistic regression curve.

[0140] B) Cleavage of p-nitrophenyl Phosphate:

[0141] This assay is based on the change in absorption of thenon-physiological substrate p-nitrophenyl phosphate during cleavage tonitrophenol under standard conditions (Tonks, N. K., Diltz, C. D:,Fischer, E. H. J. Biol. Chem. 263: 6731-6737, 1988; Burke T. R., Ye, B.,Yan, X. J., Wang, S. M., Jia, Z. C., Chen, L., Zhang, Z. Y., Barford, D.Biochemistry 35: 15989-15996, 1996). The inhibitors, at a suitabledilution, are pipetted to the reaction mixtures containing 0.5-5 mM ofp-nitrophenyl phosphate. The following buffers were used (total volume100 μl): (a) 100 mM sodium acetate (pH 5.5), 50 mM NaCl, 0.1% (w/v)bovine serum albumin, 5 mM glutathione, 5 mM DTT, 0.4 mM EGTA and 1 mMEDTA; (b) 50 mM Hepes/KOH (pH 7.4), 100 mM NaCl, 0.1% (w/v) bovine serumalbumin, 5 mM glutathione, 5 mM DTT and 1 mM EDTA. The reaction wasstarted by addition of enzyme and carried out in microtiter plates at25° C. for 1 h. The reaction was terminated by addition of 100 μl of 0.2N NaOH. The enzyme activity was determined by measuring the absorptionat 405 nm, with suitable corrections for the absorption of the testsubstances and of p-nitrophenyl phosphate. The results were expressed inpercent of the control by comparing the amount of p-nitrophenol formedin the samples treated with test substance (nmol/min/mg of protein) withthe amount in the untreated samples. Mean values and standard deviationswere calculated and the IC50 values were determined by regressionanalysis of the linear portion of the inhibition curves.

[0142] The test results show that the compounds of the formula Iaccording to the invention have an inhibitory effect on thephosphotyrosine phosphatase 1B (PTP1B). It is known that PTP1B plays animportant role in intracellular signal cascades. The compounds aretherefore suitable for treating in particular, type 1 and 2 diabetes,insulin resistance and pathological obesity. Owing to the fact that theyinhibit PTP1B, the compounds are also suitable for treatinghyperglycemia, hypertension, atherosclerosis, immune systemdysfunctions, autoimmune diseases, allergic diseases such as asthma,osteoporosis, proliferation disturbances, such as cancer and psoriasis,diseases with reduced or increased production of growth factors,hormones or cytokines which effect the release of growth hormones,disorders of the nervous system, such as Alzheimer's disease andschizophrenia, and infectious diseases.

[0143] Preparation of Exemplary Compounds (Numeration According to Table1):

[0144] Below, the preparation of some compounds is described in detail;the other compounds of the formula I were obtained in a similar manner:

[0145] Compound 1: 1,3-Dihydrobenzo[1,2,5]thiadiazole 2,2-dioxide

[0146] A solution of 1,2-phenylenediamine (91 mg, 0.84 mmol) andsulfamide (81 mg, 0.84 mmol) in diglyme (2.5 ml) is stirred at 155° C.for 1.5 h. After cooling to RT, the reaction solution is poured intoice-water (15 ml) and the product is extracted with ethyl acetate. Thesolvent is distilled off under reduced pressure and the red residue ispurified by flash chromatography (1:1 ethyl acetate/toluene).

[0147] Yield: 41 mg (35%).

[0148]¹H-NMR (D₆-DMSO): δ 10.8 (s, 2H, NH), 6.88 (m, 2H) aryl, 6.8 (m,2H) aryl. MS (ESI-MS) 171.1 (M+1).

[0149] Compound 2: 6-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide

[0150] N-(2-Hydroxy-4-methylphenyl)4-methylbenzenesulfonamide Pyridine(810 μl) and then, a little at a time, p-toluenesulfonyl chloride (1.91g, 10 mmol) are added to a solution of 2-amino-5-methylphenol (1.23 g,10 mmol) in CH₂Cl₂ (20 ml). The reaction mixture is stirred at 40° C.for 4 h. The solvent is distilled off under reduced pressure, ethylacetate is added to the residue and the solid is filtered off withsuction.

[0151] Yield: 2.32 g (83%)

[0152] 6-Methyl-3-(toluene-4-sulfonyl)-3H-benzo[1,2,3]oxathiazole2,2-dioxide

[0153] At −78° C., a solution of sulfuryl chloride (450 μl, 5.41 mmol)in CH₂Cl₂ (10 ml) is slowly added dropwise to a solution ofN-(2-hydroxy-4-methylphenyl)-4-methyl-benzenesulfonamide (1.5 g, 5.41mmol) and triethylamine (1.5 ml), and the mixture is stirred at −78° C.for one hour. After thawing to RT, the solvent is distilled off underreduced pressure and the residue is purified by RP chromatography.

[0154] Yield: 592 mg (32%).

[0155] 6-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide

[0156] 6-Methyl-3-(toluene-4-sulfonyl)-3H-benzo[1,2,3]oxathiazole2,2-dioxide (100 mg, 0.295 mmol) is dissolved in acetonitrile (5 ml). Asolution of sodium azide (of 20 mg, 0.29 mmol of sodium azide in 1 ml ofH₂O) is added to this solution, and the mixture is stirred at RTovernight. The mixture is then stirred at 60° C. for 1 h, the solvent isdistilled off under reduced pressure and the residue is purified by RPchromatography.

[0157] Yield: 47 mg (85%).

[0158]¹H-NMR (D₆-DMSO): δ 6.51 (d, 1H, aryl), 6.45 (d, 1H, aryl), 6.29(m, 1H, aryl), 2.14 (s, 3H, CH₃).

[0159] MS (ESI-MS, ES-) 184.9 (M−1).

[0160] Compound 3: 5-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide

[0161] 5-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide was synthesizedstarting with 2-amino-4-methylphenol, according to the sequencedescribed under example 2.

[0162]¹H-NMR (D₆-DMSO): δ 6.53 (d, 1H, aryl), 6.23 (m, 1H, aryl), 6.10(dd, 1H, aryl), 2.13 (s, 3H, CH₃).

[0163] MS (ESI-MS, ES-) 184.9 (M−1).

[0164] Compound 4: 1H-3-Oxa-2-thia-1-azacyclopenta[a]naphthyl2,2-dioxide

[0165] 1H-3-Oxa-2-thia-1-azacyclopenta[a]naphthyl 2,2-dioxide wassynthesized from 1-aminonaphthyl-2-ol, according to the sequencedescribed under example 2.

[0166]¹H-NMR (D₆-DMSO): δ 7.8 (dd, 1H, aryl), 7.66 (dd, 1H, aryl), 7.23(m, 2H, aryl), 7.1 (d, 1H aryl), 6.9 (d, 1H, aryl).

[0167] MS (ESI-MS, ES-) 221 (M−1).

[0168] Compound 5: 6-Nitro-3H-benzo[1,2,3]oxathiazole 2,2-dioxide

[0169] A solution of 2-amino-5-nitrophenol (7.7 g, 50 mmol) inacetonitrile (300 ml) is treated with N-ethyldiisopropylamine (18.7 ml,11.0 mmol) and N,N′-sulfuryldiimidazole (10.8 g, 55 mmol) and boiled atreflux for 18 h. After cooling to RT, the solvent is distilled off underreduced pressure, the residue is taken up in 1 N HCl and the product isextracted with ethyl acetate. The product is then purified by flashchromatography (17:2:1, EtOAc/MeOH/H₂O).

[0170] Yield: 8.3 g (76.9%).

[0171]¹H-NMR (D₆-DMSO): δ 7.6 (dd, 1H, aryl), 7.58 (s, 1H, aryl), 6.55(d, 1H, aryl).

[0172] MS (ESI-MS, ES-) 214.9 (M−1).

[0173] Compound 6: 6-Amino-3H-benzo[1,2,3]oxathiazole 2,2-dioxide

[0174] A solution of 6-nitro-3H-benzo[1,2,3]oxathiazole 2,2-dioxide(example 5) (8.1 g, 37 mmol) in methanol (250 ml) is hydrogenated atatmospheric pressure in the presence of Pd—C. The catalyst is thenfiltered off, the clear solution is treated with methanolic HCl (1 N)and the solvent is distilled off under reduced pressure. The residue isdissolved in ethanol and the product crystallizes after addition ofdiethyl ether.

[0175] Yield: 3.95 g (57.3%)

[0176] Compound 7: Methyl2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-5-carboxylate

[0177] 3 g of methyl 3-amino-4-hydroxybenzoate (0.018 mol), 3.9 g ofsulfonyidiimidazole (0.02 mol) and 3 g of DBU (0.02 mol) are dissolvedin 50 ml of acetonitrile and the solution is degassed and then heated atboiling point for 3 h.

[0178] For work-up, the solution is diluted with 120 ml of ethyl acetateand extracted with 50 ml of 1 N HCl. The organic phase is dried overmagnesium sulfate and the solvent is distilled off under reducedpressure.

[0179] The crude product is used without purification for the next step.

[0180] Yield: 3.6 g (88%)

[0181]¹H-NMR (D6-DMSO): δ 7.55 (dd, 1H, aromat.), 7.45 (d, 1H, aromat.),7.23 (d, 1H, aromat.), 3.85 (s, 3H, OMe). MS (ESI-MS) 230.1 (M+1).

[0182] Compound 8:2,2-Dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-5-carboxylic Acid

[0183] 3.3 g of compound 1 (21 mmol) are dissolved in a solution of 1.25g of NaOH in 70 ml of water. The reaction mixture is stirred at 25° C.for 4 h.

[0184] The mixture is then acidified to pH 2 using 2N HCl and evaporatedto dryness. To remove the NaCl, the residue is taken up in 150 ml ofacetone and filtered, and the solvent is distilled off. The crudeproduct is used without purification for the next step.

[0185] Yield: 2.3 g (75%)

[0186]¹H-NMR (D6-DMSO): δ 7.54 (dd, 1H, aromat.), 7.40 (d, 1H, aromat.),7.27 (d, 1H, aromat.). MS (ESI-MS) 216.1 (M+1).

[0187] Compound 9:N-[2-(3,4-Bisbenzyloxyphenyl)ethyl]-2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-5-carboxamide

[0188] A solution of 100 mg of compound 3 (0.46 mmol), 160 mg of2-(3,4-bisbenzyloxyphenyl)ethylamine hydrochloride (0.6 mmol), 115 mg ofEDC (0.6 mmol), 81 mg of HOBT and 260 mg of ethyldiisopropylamine in 2ml of DMF is stirred at 25° C. for 5 h.

[0189] The mixture is then diluted with 20 ml of ethyl acetate andextracted with 10 ml of 2N HCl. The organic phase is dried overmagnesium sulfate and the solvent is distilled off. The crude product ispurified by HPLC (RP18, acetonitrile/water 0.1% TFA).

[0190] Yield: 66 mg (40%).

[0191]¹H-NMR (D6-DMSO): δ 8.49 (t, 1H, NH), 7.46-7.23 (m, 13H, aromat.),6.97 (d, 2H, aromat.), 6.74 (dd, 1H, aromat.), 5.08 (s, 4H, OCH₂), 3.43(dt, 2H, NCH₂), 2.74 (2H, t, CH₂). MS (ESI-MS) 531.2 (M+1).

[0192] Compound 10:N-(4-Octyloxybenzyl)-2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-5-carboxamide4

[0193] Compound 4 is prepared as described for compound 3.

[0194] Yield: 63 mg (52%)

[0195]¹H-NMR (D6-DMSO): δ 8.95 (t, 1H, NH), 7.52 (dd, 1H, aromat.), 7.45(d, 1H, aromat.), 7.3 (d, 1H, aromat.), 7.22 (d, 2H, aromat.), 6.86 (d,2H, aromat.), 4.37 (d, 2H, NCH₂), 3.91 (t, 2H, OCH₂), 1.65 (m, 2H, CH₂),1.45-1.2 (m, 10H, CH₂), 0.86 (t, 3H, CH₃). MS (ESI-MS) 433.2 (M+1).

[0196] Compound 11:N-Hexadecyl-2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-5-carboxamide5

[0197] Compound 5 is prepared as described for compound 3.

[0198] Yield: 51 mg (26%)

[0199]¹H-NMR (D6-DMSO): δ 8.35 (t, 1H, NH), 7.38 (d, 1H, aromat.), 734(s, 1H, aromat.), 7.2 (d, 1H, aromat.), 3.21 (dt, 2H, NCH₂), 1.5 (m, 2H,CH₂), 1.4 (m, 26H, CH₂), 0.85 (t, 3H, CH₃). MS (ESI-MS) 439.3 (M+1).

[0200] Compound 12: Methyl2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-6-carboxylate 6

[0201] Compound 6 is prepared as described for compound 1.

[0202] Yield: 3.35 g (82%)

[0203]¹H-NMR (D6-DMSO): δ 7.43 (dd, 1H, aromat.), 7.19 (d, 1H, aromat.),6.53 (d, 1H, aromat.). MS (ESI-MS) 227.9 (M−1).

[0204] Compound 13:2,2-Dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-6-carboxylic acid 7

[0205] Compound 7 is prepared from 6 as described for compound 2.

[0206] Yield: 2.2 g (71%)

[0207]¹H-NMR (D6-DMSO): δ 7.46 (dd, 1H, aromat.), 7.25 (d, 1H, aromat.),6.46 (d, 1H, aromat.) 3.73 (s, 3H, Ome). MS (ESI-MS) 213.9 (M−1).

[0208] Compound 14:N-[2-(3,4-Bisbenzyloxyphenyl)ethyl]-2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-6-carboxamide8

[0209] Compound 8 is prepared from 7 as described for compound 3.

[0210] Yield: 4,1 g (25%)

[0211]¹H-NMR (D6-DMSO): δ 8.33 (t, 1H, NH), 7.55 (m, 2H, aromat.),7.45-7.3 (m, 10H, aromat.), 6.96 (d, 2H, aromat.), 6.86 (d, 1H,aromat.), 6.74 (dd, 1H, aromat.), 5.08 (s, 4H, OCH₂), 3.41 (dt, 2H,NCH₂), 2.73 (2H, t, CH₂). MS (ESI-MS) 531.3 (M+1).

[0212] Compound 15:N-(5-Phenylsulfanyl-1H-benzoimidazol-2-ylmethyl)-2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-6-carboxamide9

[0213] Compound 9 is prepared from 7 as described for compound 3.

[0214] Yield: 6,9 g (34%)

[0215]¹H-NMR (D6-DMSO): δ 8.96 (t, 1H, NH), 7.75 (d, 1H, aromat.), 7.61(d, 1H, aromat.), 7.46, (m, 2H, aromat.) 7.41-7.3 (m, 6H, aromat.), 6.55(d, 1H, aromat.), 4.81 (d, 2H, NCH₂). MS (ESI-MS) 453.2 (M+1).

[0216] Additional advantages, features and modifications will readilyoccur to those skilled in the art. Therefore, the invention in itsbroader aspects is not limited to the specific details, andrepresentative devices, shown and described herein. Accordingly, variousmodifications may be made without departing from the spirit or scope ofthe general inventive concept as defined by the appended claims andtheir equivalents.

[0217] As used herein and in the following claims, articles such as“the”, “a” and “an” can connote the singular or the plural.

[0218] All documents referred to herein are specifically incorporatedherein by reference in their entireties.

We claim:
 1. A compound of the formula I

in which X is CH₂, O, N; Y is CH₂, O, N; R1, R2, R3 are eachindependently of one another H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl,CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;O—(C₁-C₆)alkyl; (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkyl-COOH, (C₁-C₆)alkyl-aryl, where aryl may be phenyl,naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in eachcase be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;Phenyl, biphenyl, 1- or 2-naphthyl, 2-,3- or 4-pyridyl, 2- or 3-furanylor 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl,furanyl or thienyl rings may in each case be mono- to trisubstituted byF, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂,NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; (C₃-C₁₈)cycloalkyl, wherein the alkyl radicals one or more hydrogens may be replaced by fluorineor one hydrogen may be replaced by OH, (C₁-C₆)alkyl-phenyl orO—(C₁-C₆)alkyl-phenyl, NCO, NSO₃—(C₁-C₁₀)alkyl; or in each case two ofthe radicals R1 and R2 or R2 and R3 or R1 and R3 together form a fusedaryl radical, where aryl may be phenyl, naphthyl, biphenyl, thienyl orpyridyl and the aryl moiety may in each case be mono- to trisubstitutedby F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂,NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; or its physiologicallyacceptable salts or prodrugs.
 2. A compound of the formula I as claimedin claim 1, wherein X is O, N; Y is O, N; R1 is H, F, Cl, Br, I, NH₂,OH, NO₂, COOH; COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl,CONH(C₁-C₁₆)alkenyl, CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono-to trisubstituted by O-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;O—(C₁-C₆)alkyl; (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkyl-COOH, (C₁-C₆)alkyl-aryl, where aryl may be phenyl,naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in eachcase be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanylor 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl,furanyl or thienyl rings may in each case be mono- to trisubstituted byF, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂,NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; (C₃-C₁₈)cycloalkyl, wherein the alkyl radicals one or more hydrogens may be replaced by fluorineor one hydrogen may be replaced by OH, (C₁-C₆)alkyl-phenyl orO—(C₁-C₆)alkyl-phenyl, NCO, NSO₃—(C₁-C₁₀)alkyl; R2 is H, F, Cl, Br, I,NH₂, OH, NO₂, COOH; COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl,CONH(C₁-C₁₆)alkenyl, CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono-to trisubstituted by O-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;O—(C₁-C₆)alkyl; (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkyl-COOH, (C₁-C₆)alkyl-aryl, where aryl may be phenyl,naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in eachcase be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanylor 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl,furanyl or thienyl rings may in each case be mono- to trisubstituted byF, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂,NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; (C₃-C₁₈)cycloalkyl, wherein the alkyl radicals one or more hydrogens may be replaced by fluorineor one hydrogen may be replaced by OH, (C₁-C₆)alkyl-phenyl orO—(C₁-C₆)alkyl-phenyl, NCO, NSO₃—(C₁-C₁₀)alkyl; R3 is H, F, Cl, Br, I,NH₂, OH, NO₂, COOH; COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl,CONH(C₁-C₁₆)alkenyl, CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono-to trisubstituted by O-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;O—(C₁-C₆)alkyl; (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkyl-COOH, (C₁-C₆)alkyl-aryl, where aryl may be phenyl,naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in eachcase be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanylor 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl,furanyl or thienyl rings may in each case be mono- to trisubstituted byF, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂,NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; (C₃-C₁₈)cycloalkyl, wherein the alkyl radicals one or more hydrogens may be replaced by fluorineor one hydrogen may be replaced by OH, (C₁-C₆)alkyl-phenyl orO—(C₁-C₆)alkyl-phenyl, NCO, NSO₃—(C₁-C₁₀)alkyl; or its physiologicallyacceptable salts or prodrugs.
 3. A compound of the formula I as claimedin claim 1, wherein X is O, N; Y is N; R1 is H, F, Cl, Br, I, NH₂, OH,NO₂, COOH; COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl,CONH(C₁-C₁₆)alkenyl, CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono-to trisubstituted by O-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;O—(C₁-C₆)alkyl; (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkyl-COOH, (C₁-C₆)alkyl-aryl, where aryl may be phenyl,naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in eachcase be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-CO₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanylor 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl,furanyl or thienyl rings may in each case be mono- to trisubstituted byF, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂,NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; (C₃-C₁₈)cycloalkyl, wherein the alkyl radicals one or more hydrogens may be replaced by fluorineor one hydrogen may be replaced by OH, (C₁-C₆)alkyl-phenyl orO—(C₁-C₆)alkyl-phenyl, NCO, NSO₃—(C₁-C₁₀)alkyl; R2 is H, F, Cl, Br, I,NH₂, OH, NO₂, COOH; COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl,CONH(C₁-C₁₆)alkenyl, CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono-to trisubstituted by O-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, —COO(C₁-C₆)alkyl, CONH₂;O—(C₁-C₆)alkyl; (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkyl-COOH, (C₁-C₆)alkyl-aryl, where aryl may be phenyl,naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in eachcase be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanylor 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl,furanyl or thienyl rings may in each case be mono- to trisubstituted byF, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂,NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; (C₃-C₁₈)cycloalkyl, wherein the alkyl radicals one or more hydrogens may be replaced by fluorineor one hydrogen may be replaced by OH, (C₁-C₆)alkyl-phenyl orO—(C₁-C₆)alkyl-phenyl, NCO, NSO₃—(C₁-C₁₀)alkyl; R3 is COO(C₁-C₆)alkyl,CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl, CONH(C₁-C₆)alkyl-phenyl,where phenyl may be mono- to trisubstituted by O-(C₁-C₁₀)alkyl orO—(C₁-C₁₀)alkyl-phenyl, CONH(C₁-C₆)alkyl-benzimidazole, where thebenzimidazole ring may be mono- to trisubstituted by S-phenyl, whereinthe S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH,COO(C₁-C₆)alkyl, CONH₂; O—(C₁-C₆)alkyl; (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH, (C₁-C₆)alkyl-aryl, where aryl may bephenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety mayin each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂,CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl,CONH₂; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl,pyridyl, furanyl or thienyl rings may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; (C₃-C₁₈)cycloalkyl,where in the alkyl radicals one or more hydrogens may be replaced byfluorine or one hydrogen may be replaced by OH, (C₁-C₆)alkyl-phenyl orO—(C₁-C₆)alkyl-phenyl, NCO, NSO₃—(C₁-C₁₀)alkyl; or its physiologicallyacceptable salts or prodrugs.
 4. A compound of the formula I as claimedin claim 1, wherein X is O; Y is N; R1 is H, F, Cl, Br, I, NH₂, OH, NO₂,COOH; COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl,CONH(C₁-C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO-(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;O—(C₁-C₆)alkyl; (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkyl-COOH, (C₁-C₆)alkyl-aryl, where aryl may be phenyl,naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in eachcase be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanylor 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl,furanyl or thienyl rings may in each case be mono- to trisubstituted byF, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂,NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; (C₃-C₁₈)cycloalkyl, wherein alkyl radicals one or more hydrogens may be replaced by fluorine orone hydrogen may be replaced by OH, (C₁-C₆)alkyl-phenyl orO—(C₁-C₆)alkyl-phenyl, NCO, NSO₃—(C₁-C₁₀)alkyl; R2 is F, Cl, Br, I, NH₂,OH, NO₂, COOH; COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₁₆)alkyl,CONH(C₁-C₁₆)alkenyl, CONH(C₁-C₆)alkyl-phenyl, where the phenyl may bemono- to trisubstituted by O—(C₁-C₁₀)alkyl or O—(C₁-C₁₀)alkyl-phenyl,CONH(C₁-C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;O—(C₁-C₆)alkyl; (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkyl-COOH, (C₁-C₆)alkyl-aryl, where aryl may be phenyl,naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in eachcase be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂;Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanylor 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl,furanyl or thienyl rings may in each case be mono- to trisubstituted byF, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂,NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; (C₃-C₁₈)cycloalkyl, wherein the alkyl radicals one or more hydrogens may be replaced by fluorineor one hydrogen may be replace by OH, (C₁-C₆)alkyl-phenyl orO—(C₁-C₆)alkyl-phenyl, NCO, NSO₃—(C₁-C₁₀)alkyl; R3 is COO(C₁-C₆)alkyl,CONH₂, CONH(C₁-C₁₆)alkyl, CONH(C₁-C₁₆)alkenyl, CONH(C₁-C₆)alkyl-phenyl,where phenyl may be mono- to trisubstituted by O-(C₁-C₁₀)alkyl orO—(C₁-C₁₀)alkyl-phenyl, CON H(C₁-C₆)alkyl-benzimidazole, where thebenzimidazole ring may be mono- to trisubstituted by S-phenyl, whereinthe S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH,COO(C₁-C₆)alkyl, CONH₂; O—(C₁-C₆)alkyl; (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkyl-COOH, (C₁-C₆)alkyl-aryl, where aryl may bephenyl, naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety mayin each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂,CN, OCF₃, O—(C₁-C₁₀)alkyl, NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl,CONH₂; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl,pyridyl, furanyl or thienyl rings may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₁₀)alkyl,NH₂, NH(C₁-C₆)alkyl, COOH, COO(C₁-C₆)alkyl, CONH₂; (C₃-C₁₈)cycloalkyl,where in the alkyl radicals one or more hydrogens may be replaced byfluorine or one hydrogen may be replaced by OH, (C₁-C₆)alkyl-phenyl orO—(C₁-C₆)alkyl-phenyl, NCO, NSO₃—(C₁-C₁₀)alkyl; or its physiologicallyacceptable salts or prodrugs.
 5. A pharmaceutical composition comprisingan effective amount of at least one compound as claimed in claim 1 and apharmaceutically acceptable excipient.
 6. A method of inhibiting aPTPase comprising administering to a subject in need thereof aneffective amount of one or more compounds of claim
 1. 7. The method ofclaim 6, wherein the PTPase is PTP1B, CD45, LAR, SHP-1, SHP-2, PTPa orHePTP.
 8. A method of treating type 1 diabetes comprising administeringto a subject in need thereof an effective amount of one or morecompounds of claim
 1. 9. A method of treating type 2 diabetes comprisingadministering to a subject in need thereof an effective amount of one ormore compounds of claim
 1. 10. A method of treating insulin resistancecomprising administering to a subject in need thereof an effectiveamount of one or more compounds of claim
 1. 11. A method of treatingpathological obesity comprising administering to a subject in needthereof an effective amount of one or more compounds of claim
 1. 12. Amethod of preparing a pharmaceutical composition comprising the steps ofmixing one or more compounds of claim 1 with one or morepharmaceutically acceptable excipients and bringing this mixture into aform suitable for administration.